Research: Focal and segmental glomerulosclerosis (FSGS) is an important clinicopathologic entity, with an incidence that is estimated at seven per million individuals. It is responsible for 5-20% of all cases of end stage kidney disease (ESKD) in the United States and is second only to urogenital and kidney malformation as a cause of ESKD in children. The pathogenesis of FSGS is not well defined. Recent results from positional cloning of novel genes mutated in nephrotic syndrome and FSGS have provided important insights into the pathogenesis of the disease, including a strong link between FSGS and the podocyte. Recently, the applicant defined a new locus on chromosome 2p for FSGS in a large kindred with 13 affected individuals. Unveiling the gene that is mutated in this family will further our understanding of the pathogenesis of FSGS and has the potential to lead to rational approaches to its prevention and therapy. The overall objective of this study is to investigate the molecular defects associated with an inherited form of familial FSGS using candidate gene strategies. Specific aim 1: To perform fine mapping of the new FSGS locus on chromosome 2p. We will narrow the minimal candidate region (MCR) using polymorphic markers and haplotype analysis. Specific aim 2: To perform candidate gene analysis in the minimal candidate region (MCR) on chromosome 2p. All suitable genes in the MCR will be identified as candidates and screened for mutations to identify the disease-causing mutation in family 6543 with familial FSGS. To establish the causality of the gene mutation, in-vitro and in-vivo functional studies will be performed using cell biology approaches and mouse models appropriate to the function of the gene. The candidate: The candidate's primary goal in applying for a K08 award is to become a successful and independent investigator in the study of the molecular pathogenesis of FSGS. Environment: The study will be carried out in the state-of-the-art multidisciplinary Center for Human Genetics at Duke University Medical Center. The nephrology program at Duke University has 24 faculty with integrated and diverse clinical and research interests. The mentor and co-mentor are known experts in monogenic kidney diseases, angiotensin, podocyte biology research and mouse models of kidney disease. PUBLIC HEALTH RELEVANCE: The studies outlined in this proposal will provide an outstanding training opportunity for the applicant. In addition, the studies outlined in this proposal will provide further insight into our understanding of the pathogenetic and molecular basis of familial FSGS and possibly, the management and prevention of the more common idiopathic FSGS.